Mutations

APP V717L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1):
Genomic Mutation Name (NT1):
dbSNP ID: rs63750264
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GTC to CTC

Findings

This was the fourth AD-associated mutation discovered that involves codon 717 in APP. It was first reported in an American family in which the proband was diagnosed with AD at age 38. Her presentation was typical for her family, with short-term memory problems appearing in the mid to late thirties with gradual deterioration over approximately ten years. The mean age of onset in this family was 38 years (range: 35 to 39 years) based on data from four affected family members (Murrell et al., 2000).

Another kindred, known as "Family 171", was also found to carry this mutation. This Caucasian family of English ancestry had a later age of onset. The mean age of onset for the seven affected family members was 50 years (range: 48 to 57 years). The mean age at death was 61 years (range: 57 to 68 years). In addition to progressive memory impairment typical of AD, some members of this family also experienced seizures and hallucinations (Godbolt et al., 2006).

Two additional unrelated patients of German origin were also found to carry this mutation. One patient, identified as P. 43, had dementia onset at age 50 and a family history of dementia. The other patient, identified as P. 83, had dementia onset at age 43 and a family history of dementia (Finckh et al., 2005).

This mutation was detected in a Japanese family affected by early onset Alzheimer’s disease. The reported pedigree shows nine affected family members over three generations. The average age at onset in this family was 47.1 ± 3.1 years (range: 42 to 52 years). Typical of his family, the proband developed short term memory loss and concentration deficits at age 45.  Other symptoms in this family included psychiatric symptoms (e.g. depression, irritability, emotional lability), seizures, myoclonus, gait disturbance, and pyramidal signs. The mutation was not detected in 50 unrelated controls. MRI showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices (Abe et al., 2012).

An additional kindred is reported by Ghetti et al., 2008.

Neuropathology

MRI of affected members of the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices (Abe et al., 2012).

Biological Effect

In primary mouse neurons this mutation increases the Aβ42/Aβ40 ratio by increasing levels of Aβ42 and decreasing levels of Aβ40 (De Jonghe et al., 2001).

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References

Paper Citations

  1. . Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol. 2000 Jun;57(6):885-7. PubMed.
  2. . A second family with familial AD and the V717L APP mutation has a later age at onset. Neurology. 2006 Feb 28;66(4):611-2. PubMed.
  3. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  4. . Phenotypical difference of Amyloid Precursor Protein (APP) V717L mutation in Japanese family. BMC Neurol. 2012 Jun 15;12(1):38. PubMed.
  5. . Familial Alzheimer disease associated with the V717L amyloid precursor protein gene mutation: Neuropathological characterization. Alzheimer's & Dementia 4 Supp 2: T585, 2008.
  6. . Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001 Aug 1;10(16):1665-71. PubMed.

Further Reading

Papers

  1. . Presymptomatic Genetic Testing with an APP Mutation in Early-Onset Alzheimer Disease: A Descriptive Study of Sibship Dynamics. Journal of Genetic Counseling, Volume 9, Issue 4 , pp 327-41

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol. 2000 Jun;57(6):885-7. PubMed.

Other mutations at this position

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